The concept of genetic therapies for providing intracellular immunity to viral infection have been entertained for a number of years (see Baltimore, 1988; Szydalski, 1992). Gene therapy has recently received more attention for its potential utility in the treatment of HIV infection (Sarver and Rossi, 1993). A number of different inhibitory agents have been tested for their ability to confer resistance to HIV-1, including anti-sense RNA, ribozymes, TAR or RRE decoys, trans-dominant mutant HIV genes and conditionally lethal toxins (reviewed in Sarver and Rossi, 1993).
RNA-based strategies, such as anti-sense or ribozymes, have the dual advantage of being sequence specific, theoretically eliminating unwanted toxicities, as well as not producing potentially immunogenic proteins. A single ribozyme molecule is capable of irreversibly inactivating multiple target RNA molecules by sequential cycles of binding, cleavage and release. Even in the absence of multiple substrate turnover, ribozymes functionally inactivate target RNAs via cleavage (Zaug and Cech, 1986; Uhlenbeck, 1987; Castanotto et al., 1992).
Recently it has been discovered that individuals harboring a 32-base homozygous deletion in the CCKR-5 (also known as CCR5) gene are not subject to an infection by an M-tropic HIV-1 strain. Moreover, heterozygotes are long term survivors, which suggests that a defect in the CCR5 expression may interfere with the normal progression of AIDS. The protein encoded by the 32-based deletion gene is severely truncated, undetectable at the cell surface and with no obvious phenotype in homozygous individuals. This suggests that the inhibition of the CCR5 expression at the cell surface should affect the HIV-1 entry.